We have investigated the expression of the HIV co-receptors CXCR4 and CCR5 in peripheral blood-derived CD34+ progenitor cells and assessed infectivity of these cells by different strains of HIV. The CD34+ progenitor cell population is a heterogeneous mixture of progenitors. A minor percent of CD34+ cells co-express the CD4+ receptor. The CD34+CD4+ population represents both totipotent progenitors responsible for maintaining the hematopoietic steady state and the multipotent pre-lymphoid subset. How HIV affects these progenitor cell subpopulations in terms of direct infection, the establishment of viral reservoirs, trafficking of infected cells, self renewal/differentiation, and cell growth and function remains to be determined. The capacity for productive HIV infection of bone marrow derived progenitor cells has been controversial and has been variably reported as occurring in only a subset of HIV seropositive individuals, or in CD34+ progenitor cells co-expressing CD4+, or without evidence of productive infection. HIV-induced pro-inflammatory cytokines and viral proteins have been shown to affect the clonogenic potential and survival of bone marrow derived stem cells. Peripheral blood derived CD34+ cells represent a distinct sessile progenitor cell pool which are responsible for seeding extramedullary sites of hematopoiesis. The circulating stem/progenitor cell may serve as a minor reservoir for HIV capable of trafficking the virus to diverse anatomic compartments. We have investigated the expression of the HIV co-receptors CXCR4 and CCR5 in peripheral blood derived CD34+ progenitor cells and assessed infectivity of these cells by different strains of HIV. Both CXCR4 and CCR5 are expressed on peripheral blood derived CD34+ progenitor cells. Co-receptor expression is enriched in the more primitive subset CD34+CD38- (lineage negative). Peripheral blood derived CD34+ progenitor cells can be infected with T-trophic, M-trophic and dual-trophic strains of HIV.